The present invention relates to hydroxamic acid derivatives useful as matrix metallo-proteinase inhibitors.
Extra cellular matrix, composition of connective tissue, is metabolized by a family of proteinases termed matrix metallo-proteinases. It is known that there exist 16 kinds of matrix metallo-proteinases such as collagenase (matrix metallo-proteinase-1: MMP-1), gelatinase A (matrix metallo-proteinase-2: MMP-2), stromelysin (metallo-proteinase-3: MMP-3), gelatinase B (matrix metallo-proteinase-9: MMP-9) and collagenase-3 (matrix metallo-proteinase-13: MMP-13). Extra cellular matrix is under tight control by the expression and secretion of these matrix metallo-proteinases or endogenous inhibitors such as tissue inhibitor of matrix metallo-proteinases in normal. There are many reports about relationships between diseases characterized by excessive tissue disruption and elevated activities of matrix metallo-proteinases derived form the breakdown of these control.
Elevated levels of matrix metallo-proteinases, particularly collagenase and stromelysin, have been detected in joints of osteoarthritic humans or that of rheumatoid arthritis (Arthr. Rheum., 33, 388-97 (1990); S. M. Krane et. al., xe2x80x9cModulation of matrix synthesis and in The Control of degradation in joint inflammation, The Control of Tissue Damagexe2x80x9d, A. B. Glauert (ed.), Elsevier Sci. Publ., Amsterdam, 1988, Ch. 14, pp 179-95; Clin. Chim. Acta, 185, 73-80(1989); Arthr. Rheum., 27, 305-312(1984); J. Clin. Invest., 84, 678-685(1989)).
Secreted proteinases such as stromelysin, collagenase and gelatinase play an important role in processes involved in the movement of cells during metastatic tumor invasion. Indeed, there is also evidence that the matrix metallo-proteinases are overexpressed in certain metastatic tumor cell line. In this context, the enzyme functions to penetrate underlying basement membranes and allow the tumor cell to escape from the site of primary tumor formation and enter circulation (FEBS J., 5, 2145-2154(1991); Trends Genet., 6, 121-125(1990); Cancer Res., 46, 1-7(1986); Cell, 64, 327-336(1990); Cancer and Metastasis Rev., 9, 305-319(1990)).
Both collagenase and stromelysin activities are observed in fibroblasts isolated from inflamed gingiva (J. Periodontal Res., 16, 417-424(1981)). Enzyme levels have been correlated to the severity of gum disease (J. Periodontal Res., 22, 81-88 (1987)).
Collagenase-3 (matrix metalloproteinase-13: MMP-13) is expressed in synovia of rheumatoid arthritis and chondrocyte of human osteoarthritis (J. Clin. Invest., 97, 2011-2019(1996); J. Rheumatol., 23, 509-595(1996); J. Biol. Chem., 271, 23577-23581(1996); J. Clin. Invest., 97, 761-768(1996)). MMP-13 has a strong enzyme activity against type II collagen and aggrecan. Thus, it is suggested that MMP-13 plays an important role in osteoarthritis and rheumatoid arthritis (J. Biol. Chem., 271, 1544-1550(1996); FEBS Lett., 380, 17-20(1996)). Therefore, inhibitors to matrix metallo-proteinase are useful as therapeutic agents or prophylactic drugs for joint diseases such as osteoarthritis, rheumatoid arthritis, metastasis of tumor cell and gingivitis.
Matrix metallo-proteinases are also concerned with conversion from the latent form of tumor necrosis factor-a to the mature form (Nature, 370, 555-557(1994)), degradation of xcex1 1-antitrypsin (FEBS Lett., 279, 191-194(1991)) and processing of other matrix metallo-proteinases (Biochemistry, 29, 10261-10670(1990); J. Biol. Chem., 267, 21712-21719(1992)). Therefore, inhibitors to matrix metalloproteinase are useful as anti-inflammatory agents.
WO 96/20936 disclose novel thiazolidin-4-one derivatives which inhibit platelet-activating factor and/or 5-lipoxygenase. But, it does not disclose the compounds can inhibit matrix metallo-proteinases.
The present invention is intended to provide novel compounds useful as matrix metallo-proteinase inhibitors.
The present inventors have earnestly examined and found that hydroxamic acid derivatives have excellent inhibition activity against matrix metallo-proteinases such as MMP-3, MMP-13 and the like. Thus, the present invention has been accomplished.
That is, the present invention is as follows:
(1) A hydroxamic acid derivative represented by the formula [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof: 
wherein
X is C1-C2 alkylene which is substituted by optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; optionally substituted ortho-arylene; or optionally substituted ortho-heteroarylene;
Y1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
Y2 is O, or S;
One of R1 and R3 is xe2x80x94(CHR4)nxe2x80x94(CR5R6)xe2x80x94COxe2x80x94NHOH;
The other of R1 and R3 is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted hetero-cycloalkyl; or R2 and R3 may be taken together to be optionally substituted C1-C10 alkylidene;
R4, R5 and R6 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteraryl; or R5 may be joined with R4 or R6 to form, with the carbon atom which they attach, optionally substituted cycloalkane or optionally substituted heterocycloalkane;
n is an integer of 0 to 4;
provided that when R2 and R3 are taken together to be optionally substituted C1-C10 alkylidene, X is not methylene substituted by a phenyl or a pyridyl wherein the phenyl and the pyridyl are optionally substituted by methyl or methoxy.
(2) A hydroxamic acid derivative according to (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein
X is C1-C2 alkylene substituted by xe2x80x94Zxe2x80x94Ar; optionally substituted ortho-arylene; or optionally substituted ortho-heteroarylene;
Z is single bond or alkylene;
Ar is optionally substituted aryl or optionally substituted heteroaryl.
(3) A hydrozamic acid derivative according to (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein
X is one of the groups represented by the formulae: 
Ar1 is optionally substituted aryl or optionally substituted heteroaryl;
A1 is ortho-phenylene or monocyclic ortho-heteroarylene;
R8 and R9 are independently hydrogen or substituent.
(4) A hydroxamic acid derivative according to any one of (1)-(3) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y1 is xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94.
(5) A hydroxamic acid derivative according to any one of (1)-(4) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.
(6) A hydroxamic acid derivative according to any one of (1)-(5) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.
(7) A hydroxamic acid derivative according to (1) represented by the formula [2] or a prodrug thereof, or a pharmaceutically acceptable salt thereof: 
wherein
Y2, R4, R5 and R6 are as defined in (1);
Ar2 is optionally substituted phenyl; optionally substituted naphthyl; or optionally substituted mono or bicyclic heteroaryl;
Y3 is xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
R10 and R11 are independently hydrogen or optionally substituted alkyl;
n1 is an integer of 0, 1 or 2.
(8) A hydroxamic acid derivative according to (7) or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
wherein n1 is 0.
(9) A hydroxamic acid derivative according to (1) represented by the formula [3] or a prodrug thereof, or a pharmaceutically acceptable salt thereof: 
wherein
Y2, R4, R5 and R6 are as defined in (1);
A1, R8, and R9 are defined in (3);
R12 and R13 are independently hydrogen or optionally substituted alkyl;
Y3 is xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
n2 is an integer of 0, 1 or 2.
(10) A hydroxamic acid derivative according to (1) represented by the formula [3xe2x80x2] or a prodrug thereof, or a pharmaceutically acceptable salt thereof: 
wherein
Y2, R4, R5 and R6 are as defined in (1);
A1 is defined in (3);
Y3, n2, R12 and R13 are defined in (9);
R14 is hydrogen or substituent;
R15 is substituent.
(11) A hydroxamic acid derivative according to (9)-(10) or a prodrug thereof or a pharmaceutically acceptable salt thereof;
wherein n2 is 0, and R12 and R13 are independently hydrogen or substituted alkyl group.
(12) A hydroxamic acid derivative according to any one of claim 1-11 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y2 is xe2x80x94Oxe2x80x94.
(13) A pharmaceutical composition containing a hydroxamic acid derivative according to any one of (1)-(12) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
(14) A method of inhibiting matrix metallo-proteinases which comprises treating the matrix metallo-proteinases with a hydroxamic acid derivative according to any one of (1)-(12) or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
(15) A method of inhibiting matrix metallo-proteinases according to (14), wherein the matrix metallo-proteinases are matrix metallo-proteinase 3 and/or 13.
(16) A method of treating a disease associated with excess or undesired matrix metallo-proteinases which comprises administering an effective amount of a hydroxamic acid derivative according to any one of (1)-(12) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
(17) A method of treating a disease associated with excess or undesired matrix metallo-proteinases according to (16), wherein the matrix metallo-proteinases are matrix metallo-proteinase 3 and/or 13.
(18) Use of a hydroxamic acid derivative according to any one of (1)-(12) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with excess or undesired matrix metallo-proteinases.
xe2x80x9cOrtho-arylenexe2x80x9d includes C6-C10 ortho-arylene. Typical examples are ortho-phenylene, 1,2-naphthalenediyl, 2,3-naphthalenediyl and the like. Preferable is ortho-phenylene.
xe2x80x9cOrtho-heteroarylenexe2x80x9d includes mono or bicyclic 5- or 6-membered ortho-heteroarylene containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms. Mono or bicyclic 5-membered ortho-heteroarylene includes, for example, monocyclic 5-membered ortho-heteroarylene containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as pyrrol-2,3-diyl, pyrrol-3,4-diyl, thiophen-2,3-diyl, thiophen-3,4-diyl, furan-2,3-diyl, imidazol-4,5-diyl, pyrazol-3,4-diyl, thiazol-2,3-diyl, oxazole-2,3-diyl, isothiazol-3,4-diyl, isoxazol-3,4-diyl and the like; bicyclic 5-membered ortho-heteroarylene containing 1 or 2 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as indol-2,3-diyl, benzofurandiyl, benzothiophendiyl and the like; and the like. Mono or bicyclic 6-membered ortho-heteroarylene includes, for example, monocyclic 6-membered ortho-heteroarylene containing 1 to 3 nitrogen atoms such as pyridin-2,3-diyl, pyridin-3,4-diyl, pyrazin-2,3-diyl, pyrimidin-4,5-diyl, pyridazin-3,4-diyl and the like; bicyclic 6-membered ortho-heteroarylene containing 1 to 3 nitrogen atoms such as quinolin-2,3-diyl, isoquinolin-3,4-diyl, naphthyridin-3,4-diyl, quinoxalin-2,3-diyl and the like; and the like. Preferable ortho-heteroarylene is monocyclic 5, or 6-membered ortho-heteroarylene.
xe2x80x9cArylxe2x80x9d includes C6-C10 aryl. Typical examples are phenyl, 1-naphthyl, 2-naphthyl and the like.
xe2x80x9cHeteroarylxe2x80x9d includes, for example, mono or bicyclic 5- or 6-membered heteroaryl containing 1 to 5 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. Mono or bicyclic 5-membered heteroaryl includes, for example, monocyclic 5-membered heteroaryl containing 1 to 5 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, furazanyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, and the like; bicyclic 5-membered heteroaryl containing 1 to 5 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as indolyl, isoindolyl, benzofuryl, benzothienyl, thieno[2,3-b]thienyl and the like; and the like. Mono or bicyclic 6-membered heteroaryl includes, for example, monocyclic 6-membered heteroaryl containing 1 to 5 nitrogen atoms such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like; bicyclic 6-membered heteroaryl containing 1 to 5 nitrogen atoms such as quinolyl, phthalazinyl, isoquinolyl, naphthyridinyl, quinoxalinyl and the like; and the like.
xe2x80x9cSubstituentxe2x80x9d of the substituted aryl, the substituted heteroaryl, the substituted ortho-arylene and substituted ortho-heteroarylene, and xe2x80x9csubstituentxe2x80x9d of R8, R9, and R14 includes, for example, the following groups:
halogen; alkyl; alkenyl; alkynyl; halogenated alkyl; xe2x80x94Z1xe2x80x94Ar3; xe2x80x94Z1xe2x80x94Cy1; xe2x80x94Z1xe2x80x94N(Q2)Q1; xe2x80x94Z1xe2x80x94N(Q2)Ar3; xe2x80x94Z1xe2x80x94N(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ4xe2x80x94C(NQ3)N(Q2)Q1; xe2x80x94Z1xe2x80x94NQ4xe2x80x94C(NQ3)N(Q2)Ar3; xe2x80x94Z1xe2x80x94NQ4xe2x80x94C(NQ3)N(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ3xe2x80x94CON(Q2)Q1; xe2x80x94Z1xe2x80x94NQ3xe2x80x94CON(Q2)Ar3; xe2x80x94Z1xe2x80x94NQ3CON(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COOQ1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COOAr3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COOCy1; xe2x80x94Z1xe2x80x94OCON(Q1)Q2; xe2x80x94Z1xe2x80x94OCON(Q2)Ar3; xe2x80x94Z1xe2x80x94OCON(Q2)Cy1; xe2x80x94Z1xe2x80x94OCOOQ1; xe2x80x94Z1xe2x80x94OCOOAr3; xe2x80x94Z1xe2x80x94OCOOCy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COQ1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COAr3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COCy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SOQ1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SOAr3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SOCy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SO2Q1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SO2Ar3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SO2Cy1; xe2x80x94Z1xe2x80x94OQ1; xe2x80x94Z1xe2x80x94OAr3; xe2x80x94Z1xe2x80x94Oxe2x80x94Cy1; xe2x80x94Z1xe2x80x94OCOQ1; xe2x80x94Z1xe2x80x94OCOAr3; xe2x80x94Z1xe2x80x94OCOCy1; xe2x80x94Z1xe2x80x94COOQ1; xe2x80x94Z1xe2x80x94COOAr3; xe2x80x94Z1xe2x80x94COOCy1; xe2x80x94Z1xe2x80x94CON(Q1)Q2; xe2x80x94Z1xe2x80x94CON(Q2)Ar3; xe2x80x94Z1xe2x80x94CON(Q2)Cy1; xe2x80x94Z1xe2x80x94CON(Q2)OQ1; xe2x80x94Z1xe2x80x94CON(Q2)OAr3; xe2x80x94Z1xe2x80x94CON(Q2)OCy1; xe2x80x94Z1xe2x80x94COQ1; xe2x80x94Z1xe2x80x94COAr3; xe2x80x94Z1xe2x80x94COxe2x80x94Cy1; xe2x80x94Z1xe2x80x94C(NQ3)N(Q1)Q2; xe2x80x94C(NQ3)N(Q2)Ar3; xe2x80x94Z1xe2x80x94C(NQ3)N(Q2)Cy1; xe2x80x94Z1xe2x80x94SQ1; xe2x80x94Z1xe2x80x94SAr3; xe2x80x94Z1xe2x80x94Sxe2x80x94Cy1; xe2x80x94Z1xe2x80x94SOQ1; xe2x80x94Z1xe2x80x94SOAr3; xe2x80x94Z1xe2x80x94SOCy1; xe2x80x94Z1xe2x80x94SO2Q1; xe2x80x94Z1xe2x80x94SO2Ar3; xe2x80x94Z1xe2x80x94SO2Cy1; xe2x80x94Z1xe2x80x94SON(Q1)Q2; xe2x80x94Z1xe2x80x94SON(Q2)Ar3; xe2x80x94Z1xe2x80x94SON(Q2)Cy1; xe2x80x94Z1xe2x80x94SO2N(Q1)Q2; xe2x80x94Z1xe2x80x94SO2N(Q2)Ar3; xe2x80x94Z1xe2x80x94SO2N(Q2)Cy1; xe2x80x94Z1xe2x80x94SO3H; xe2x80x94Z1xe2x80x94OSO3H; xe2x80x94Z1xe2x80x94NO2; xe2x80x94Z1xe2x80x94CN; xe2x80x94CHO;
xe2x80x83wherein
Z1 is single bond, alkylene, alkenylene or alkynylene;
Q1, Q2, Q3, Q4 are independently hydrogen, alkyl, alkenyl, alkynyl, wherein the alkyl, the alkenyl and the alkynyl are optionally substituted by one or more groups selected from the following groups:
halogen; xe2x80x94Ar4; Cy2; xe2x80x94N(R21)R22; xe2x80x94N(R22)Ar4; xe2x80x94N(R22)Cy2; xe2x80x94NR24xe2x80x94C(NR23)N(R22)R21; xe2x80x94NR24xe2x80x94C(NR23)N(R22)Ar4; xe2x80x94NR24xe2x80x94C(NR23)N(R22)Cy2; xe2x80x94NR23xe2x80x94CON(R22)R21; xe2x80x94NR23xe2x80x94CON(R22)Ar4; xe2x80x94NR23xe2x80x94CON(R22)Cy2; xe2x80x94NR22xe2x80x94COOR21; xe2x80x94NR22xe2x80x94COOAr4; xe2x80x94NR22xe2x80x94COOCy2; xe2x80x94OCON(R22)R21; xe2x80x94OCON(R22)Ar4; xe2x80x94OCON(R22)Cy2; xe2x80x94OCOOR21; xe2x80x94OCOOAr4; xe2x80x94OCOOCy2; xe2x80x94NR22xe2x80x94COR21; xe2x80x94NR22xe2x80x94COAr4; xe2x80x94NR22xe2x80x94COCy2; xe2x80x94NR22xe2x80x94SOR21; xe2x80x94NR22xe2x80x94SOAr4; xe2x80x94NR22xe2x80x94SOCy2; xe2x80x94NR22xe2x80x94SO2R21; xe2x80x94NR22xe2x80x94SO2Ar4; xe2x80x94NR22xe2x80x94SO2Cy2; xe2x80x94OR21; xe2x80x94OAr4; xe2x80x94OCy2; xe2x80x94OCOR21; xe2x80x94OCOAr4; xe2x80x94OCOCy2; xe2x80x94COOR21; xe2x80x94COOAr4; xe2x80x94COOCy2; CON(R21)R22; xe2x80x94CON(R22)Ar4; xe2x80x94CON(R22)Cy2; xe2x80x94CON(R22)OR21; xe2x80x94CON(R22)OAr4; xe2x80x94CON(R22)OCy2; xe2x80x94COR21; xe2x80x94COAr4; xe2x80x94COCy2; xe2x80x94SR21; xe2x80x94SAr4; xe2x80x94SCy2; xe2x80x94SOR21; xe2x80x94SOAr4; xe2x80x94SOCy2; xe2x80x94SO2R21; xe2x80x94SO2Ar4; xe2x80x94SO2Cy2; xe2x80x94SON(R22)R21; xe2x80x94SON(R22)Ar4; xe2x80x94SON(R22)Cy2; xe2x80x94SO2N(R22)R21; xe2x80x94SO2N(R22)Ar4; xe2x80x94SO2N(R22)Cy2; xe2x80x94SO3H; xe2x80x94OSO3H; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CHO;
or Q1 may be Jointed with Q2 or Q3 to form, with the carbon atom which they attach, optionally substituted heterocycloalkane.
R21, R22, R23, R24, R25, R26, R27, and R28 are independently hydrogen, alkyl, alkenyl, alkynyl, or
R21 may be jointed with R23, R24 to form, with the carbon atom which they attach, heterocycloarlkane, or
R25 may be jointed with R26, R27 to form, with the carbon atom which they attach, heterocycloarlkane.
Ar3 and Ar4 are independently phenyl or heteroaryl, wherein the phenyl and the heteroaryl are optionally substituted by one or two groups selected from the following groups:
halogen; alkyl; alkenyl; alkynyl; halogenated alkyl; xe2x80x94Z2xe2x80x94N(R25)R26; xe2x80x94Z2xe2x80x94NR28xe2x80x94C(NR27)N(R26)R25; xe2x80x94Z2xe2x80x94NR27xe2x80x94CON(R26)R25; xe2x80x94Z2xe2x80x94NR26xe2x80x94COR25; xe2x80x94Z2xe2x80x94OCON(R26)R25; xe2x80x94Z2xe2x80x94NR26COR25; xe2x80x94Z2xe2x80x94NR26SOR25; xe2x80x94Z2xe2x80x94NR26xe2x80x94SO2R25; xe2x80x94Z2xe2x80x94OR25; xe2x80x94Z2xe2x80x94COOR25; xe2x80x94Z2xe2x80x94OCOR25; xe2x80x94Z2xe2x80x94OCOOR25; xe2x80x94Z2xe2x80x94CON(R26)R25; xe2x80x94Z2xe2x80x94CON(R26)OR25; xe2x80x94Z2xe2x80x94COR25; xe2x80x94Z2xe2x80x94C(NR27)N(R26)R25; xe2x80x94Z2xe2x80x94SR25; xe2x80x94Z2xe2x80x94SOR25; xe2x80x94Z2xe2x80x94SO2R25; xe2x80x94Z2xe2x80x94SON(R25)R26; xe2x80x94Z2xe2x80x94SO2N(R26)R25; xe2x80x94Z2xe2x80x94SO3H; xe2x80x94Z2xe2x80x94OSO3H; xe2x80x94Z2xe2x80x94NO2; xe2x80x94Z2xe2x80x94CN; xe2x80x94CHOxe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94:
Z2 is single bond, alkylene, alkenylene or alkynylene;
Cy1 and Cy2 are independently cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein the cycloalkyl, the cycloalkenyl, the heterocycloalkyl, and the heterocycloalkenyl are optionally substituted by one or two groups which are the same as the substituent of the substituted phenyl as used in Ar3 or Ar4.
xe2x80x9cSubstituentsxe2x80x9d of R8 and R9 may also selected from the following groups:
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94.
xe2x80x9cSubstituentxe2x80x9d of R15 includes, for example, the following groups:
xe2x80x94Z1xe2x80x94Ar3xe2x80x2; xe2x80x94Z1xe2x80x94Cy1xe2x80x2; xe2x80x94Z1xe2x80x94N(Q1)Q2; xe2x80x94Z1xe2x80x94N(Q2)Ar3; xe2x80x94Z1xe2x80x94N(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ4xe2x80x94C(NQ3)N(Q2)Q1; xe2x80x94Z1xe2x80x94NQ4xe2x80x94C(NQ3)N(Q2)Ar3; xe2x80x94Z1xe2x80x94NQ4xe2x80x94C(NQ3)N(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ3xe2x80x94CON(Q2)Q1; xe2x80x94Z1xe2x80x94NQ3xe2x80x94CON(Q2)Ar3; xe2x80x94Z1xe2x80x94NQ3xe2x80x94CON(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COOQ1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COOAr3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COOCy1; xe2x80x94Z1xe2x80x94OCON(Q1)Q2; xe2x80x94Z1xe2x80x94OCON(Q2)Ar3; xe2x80x94Z1xe2x80x94OCON(Q2)Cy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COQ1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COAr3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94COCy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SOQ1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SOAr3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SOCy1; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SO2Q1; xe2x80x94Z1xe2x80x94NQ2SO2Ar3; xe2x80x94Z1xe2x80x94NQ2xe2x80x94SO2Cy1; xe2x80x94Z1xe2x80x94OQ1xe2x80x2; xe2x80x94Z1xe2x80x94OCOQ1; xe2x80x94Z1xe2x80x94OCOAr3; xe2x80x94Z1xe2x80x94OCOCy1; xe2x80x94Z1xe2x80x94OCOOQ1; xe2x80x94Z1xe2x80x94OCOOAr3; xe2x80x94Z1xe2x80x94OCOOCy1; xe2x80x94Z1xe2x80x94COOQ1; xe2x80x94Z1xe2x80x94COOAr3; xe2x80x94Z1xe2x80x94COOCy1; xe2x80x94Z1xe2x80x94CON(Q1)Q2; xe2x80x94Z1xe2x80x94CON(Q2)Ar3; xe2x80x94Z1xe2x80x94CON(Q2)Cy1; xe2x80x94Z1xe2x80x94CON(Q1)OQ2; xe2x80x94Z1xe2x80x94CON(Q2)OAr3; xe2x80x94Z1xe2x80x94CON(Q2)OCy1; xe2x80x94Z1xe2x80x94COQ1; xe2x80x94Z1xe2x80x94COAr3; xe2x80x94Z1xe2x80x94COxe2x80x94Cy1; xe2x80x94Z1xe2x80x94C(NQ3)N(Q1)Q2; xe2x80x94Z1xe2x80x94C(NQ3)N(Q2)Ar3; xe2x80x94Z1xe2x80x94C(NQ3)N(Q2)Cy1; xe2x80x94Z1xe2x80x94SQ1xe2x80x2; xe2x80x94Z1xe2x80x94SOQ1; xe2x80x94Z1xe2x80x94SOAr3; xe2x80x94Z1xe2x80x94SOCy1; xe2x80x94Z1xe2x80x94SO2Q1; xe2x80x94Z1xe2x80x94SO2Ar3; xe2x80x94Z1xe2x80x94SO2Cy1; xe2x80x94Z1xe2x80x94SON(Q1)Q2; xe2x80x94Z1xe2x80x94SON(Q2)Ar3; xe2x80x94Z1xe2x80x94SON(Q2)Cy1; xe2x80x94Z1xe2x80x94(Q1)Q2; xe2x80x94Z1xe2x80x94SO2N(Q2)Ar3; xe2x80x94Z1xe2x80x94SO2N(Q2)xe2x80x94Cy2; xe2x80x94CHO;
xe2x80x83wherein
Q1, Q2, Q3, Q4, R21, R22, R23, R24, Z1, Ar3, Ar4, Cy1 and Cy2 are defined above.
Q1xe2x80x2 is hydrogen, alkyl, alkenyl, or alkynyl, wherein the alkyl, alkenyl, and alkynyl are substituted by one or more groups selected from the following groups:
xe2x80x94Ar4xe2x80x2; xe2x80x94Cy2; xe2x80x94N(R21)R22; xe2x80x94N(R22)Ar4; xe2x80x94N(R22)Cy2; xe2x80x94NR24xe2x80x94C(NR23)N(R22)R21; xe2x80x94NR24xe2x80x94C(NR23)N(R22)Ar4; xe2x80x94NR24xe2x80x94C(NR23)N(R22)Cy2; xe2x80x94NR23xe2x80x94CON(R22)R21; xe2x80x94NR23xe2x80x94CON(R22)Ar4; xe2x80x94NR23xe2x80x94CON(R22)Cy2; xe2x80x94NR22xe2x80x94COOR21; xe2x80x94NR22xe2x80x94COOAr4; xe2x80x94NR22xe2x80x94COOCy2; xe2x80x94OCONR21; xe2x80x94OCONAr4; xe2x80x94OCONCy2; xe2x80x94NR22xe2x80x94COR21; xe2x80x94NR22xe2x80x94COAr4; xe2x80x94NR22xe2x80x94COCy2; xe2x80x94NR22xe2x80x94SOR21; xe2x80x94NR2xe2x80x94SOAr4; xe2x80x94NR22xe2x80x94SOCy2; xe2x80x94NR22xe2x80x94SO2R21; xe2x80x94NR22xe2x80x94SO2Ar4; xe2x80x94NR22xe2x80x94SO2Cy2; xe2x80x94OCOR21; xe2x80x94OCOAr4; xe2x80x94OCOCy2; xe2x80x94COOR21; COOAr4; xe2x80x94COOCy2; xe2x80x94OCOOR21; xe2x80x94OCOOAr4; OCOOCy2; xe2x80x94CON(R21)R22; xe2x80x94CON(R22)Ar4; xe2x80x94CON(R22)Cy2; xe2x80x94CON(R22)OR21; xe2x80x94CON(R22)OAr4; xe2x80x94CON(R22)OCy2; xe2x80x94COR21; xe2x80x94COAr4; xe2x80x94COCy2; xe2x80x94SOR21; xe2x80x94SOAr4; xe2x80x94SOCy2; xe2x80x94SO2R21; xe2x80x94SO2Ar4; xe2x80x94SO2Cy2; xe2x80x94SON(R22)R21; xe2x80x94SON(R22)Ar4; xe2x80x94SON(R2)Cy2; xe2x80x94SO2N(R22)R21; xe2x80x94SO2N(R22)Ar4; xe2x80x94SO2(R22)Cy2; xe2x80x94CN; xe2x80x94CHO; xe2x80x94OH; xe2x80x94SH
Ar3xe2x80x2 and Ar4xe2x80x2 are heteroaryl, wherein the heteroaryl are optionally substituted by one or two groups which are the same as the substituent of the substituted phenyl as used in Ar3 or Ar4.
Cy1xe2x80x2 and Cy2xe2x80x2 are heterocycloalkyl or heterocycloalkenyl, wherein the heterocycloalkyl and the heterocycloalkenyl is optionally substituted by one or two groups which are the same as the substituent of the substituted phenyl as used in Ar3 or Ar4.
The number of xe2x80x9csubstituentxe2x80x9d of the substituted aryl, the substituted heteroaryl, the substituted ortho-arylene and substituted ortho-heteroarylene, and the number of xe2x80x9csubstituentxe2x80x9d of R8, R9, R14 and R15 are one, two or three, preferably one or two.
xe2x80x9cAlkylxe2x80x9d includes straight or branched C1-C6 alkyl. Typical examples are methyl, ethyl, propyl, 2-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, 2,2-dimethylpropyl, pentyl, hexyl and the like.
xe2x80x9cHalogenated alkylxe2x80x9d includes straight or branched C1-C6 alkyl substituted by one or more of halogens. Typical examples are trifluoromethyl, pentafluoroethyl, 2-chloroethyl, 3-bromopropyl, 5-fluoropentyl, 4-iodohexyl and the like.
xe2x80x9cAlkoxyxe2x80x9d includes straight or branched C1-C6 alkoxy. Typical examples are methoxy, ethoxy, propoxy, 2-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, 2,2-dimethylpropoxy, pentyloxy, hexyloxy, and the like.
xe2x80x9cAlkylthioxe2x80x9d includes straight or branched C1-C6 alkylthio. Typical examples are methylthio, ethylthio, propylthio, 2-methylethylthio, butylthio, 2-methylpropylthio, 1-methylpropylthio, 1,1-dimethylethlthio; 2,2-dimethylpropylthio, pentylthio, hexylthio, and the like.
xe2x80x9cAlkenylxe2x80x9d includes straight or branched C2-C6 alkenyl. Typical examples are vinyl, allyl, 1-propenyl, 2-butenyl and the like.
xe2x80x9cAlkynylxe2x80x9d includes straight or branched C2-C6 alkynyl. Typical examples are ethynyl, propargyl, 1-propynyl, 2-butynyl, pentynyl and the like.
xe2x80x9cAlkylenexe2x80x9d includes straight or branched C1-C6 alkylene. Typical examples are methylene, ethylene, trimethylene, 2-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
xe2x80x9cAlkenylenexe2x80x9d includes straight or branched C2-C6 alkenylene. Typical examples are vinylene, propenylene, 2-butenylene, 2-methyl-2-butenylene, 3-pentenylene, 3-hexenylene and the like.
xe2x80x9cAlkynylenexe2x80x9d includes straight or branched C2-C6 alkynylene. Typical examples are ethynylene, propynylene, 2-butynylene, 3-pentynylene, 2-methyl-3-pentynylene, 3-hexynylene and the like.
xe2x80x9cC1-C2 alkylenexe2x80x9d is methylene or ethylene.
xe2x80x9cC1-C10 alkylidenexe2x80x9d includes straight or branched C1-C10 alkylidene, preferably straight or branched C1-C6 alkylidene. Typical examples are methylidene, ethylidene, propylidene, butylidene, 2-methylbutylidene, hexylidene, octylidene, nonylidene, decylidene and the like. Preferable is methylidene.
xe2x80x9cCycloalkanexe2x80x9d includes C3-C8 cycloalkane, which can be containing 0-2 carbonyl group. Typical examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclohexanone and the like.
xe2x80x9cHeterocycloalkanexe2x80x9d includes, for example, 5- or 6-membered heterocycloalkane containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms,and the like. The sulfur atoms of xe2x80x9cHeterocycloalkanexe2x80x9d may be oxidized to form sulfoxide, or sulfone. xe2x80x9cHeterocycloalkanexe2x80x9d may also be containing 0-2 carbonyl groups. Typical examples of 5-membered heterocycloalkane containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, are pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, tetrahydrothiophene, dioxolane, pyrrolidinone, and the like. Typical examples are 6-membered heterocycloalkane containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, are piperidine, piperazine, morpholine, tetrahydropyrane, dioxane, thiomorpholine, 4-piperidone and the like.
xe2x80x9cCycloalkylxe2x80x9d includes C3-C8 cycloalkyl, which may contain 0-2 carbonyl group. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexanone-4-yl and the like.
xe2x80x9ccycloalkenylxe2x80x9d includes C3-C8 cycloalkenyl, which may contain 0-2 carbonyl group. Typical examples are cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopenten-3-one-yl and the like.
xe2x80x9cHeterocycloalkylxe2x80x9d includes, for example, 5- or 6-membered heterocycloalkyl containing 1 to 5 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. The sulfur atoms of xe2x80x9cHeterocycloalkylxe2x80x9d may be oxidized to form sulfoxide or sulfone. xe2x80x9cHeterocycloalkylxe2x80x9d may also be containing 0-2 carbonyl groups. Typical examples are 5-membered heterocycloalkyl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, are pyrrolidinyl, 2-pyrrolidinone-1-yl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, diozolanyl and the like. Typical examples are 6-membered heterocycloalkyl containing 1 or 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, are piperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 4-piperidone-1-yl and the like.
xe2x80x9cHeterocycloalkenylxe2x80x9d includes, for example, 5- or 6-membered heterocycloalkenyl containing 1 to 5 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. The sulfur atoms of xe2x80x9cHeterocycloalkenylxe2x80x9d may be oxidized to form sulfoxide or sulfone. xe2x80x9cHeterocycloalkenylxe2x80x9d may also be containing 0-2 carbonyl groups. Typical examples are 5-membered heterocycloalkenyl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, are pyrrolinyl, imidazolinyl, pyrazolinyl, dihydrofuryl, 5-pyrazolone-4-yl and the like. Typical examples are 6-membered heterocycloalkyl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, are 2,3-dihydropyridyl-, 4-pyridone-1-yl and the like.
xe2x80x9cSubstituentxe2x80x9d of the substituted alkyl, the substituted alkenyl, the substituted alkynyl, the substituted alkoxy, the substituted alkylthio, the substituted cycloalkyl, the substituted heterocycloalkyl, the cycloalkenyl, the substituted heterocycloalkenyl, the substituted cycloalkane, the substituted heterocycloalkane and the substituted C1-C10 alkylidene includes, for example, the following groups:
halogen; xe2x80x94Ar5; xe2x80x94Cy3; xe2x80x94N(Q5)Q6; xe2x80x94N(Q6)Ar5; xe2x80x94N(Q6)Cy3; xe2x80x94NQ8xe2x80x94C(NQ7)N(Q6)Q5; xe2x80x94NQ8xe2x80x94C(NQ7)N(Q6)Ar5; xe2x80x94NQ8xe2x80x94C(NQ7)N(Q6)Cy3; xe2x80x94NQ7xe2x80x94CON(Q6)Q5; xe2x80x94NQ6xe2x80x94CON(Q5)Ar5; xe2x80x94NQ7xe2x80x94CON(Q6)Cy3; xe2x80x94NQ7xe2x80x94COOQ6; xe2x80x94NQ7xe2x80x94COOAr5; xe2x80x94NQ7xe2x80x94COOCy3; xe2x80x94OCON(Q6)Q5; xe2x80x94OCON(Q6)Ar5; xe2x80x94OCON(Q6)Cy3; NQ6xe2x80x94COQ5; xe2x80x94NQ6xe2x80x94COAr5; xe2x80x94NQ6xe2x80x94COCy3; xe2x80x94NQ6xe2x80x94SOQ5; xe2x80x94NQ6xe2x80x94SOAr5; xe2x80x94NQ6xe2x80x94SOCy3; xe2x80x94NQ6xe2x80x94SO2Q5; xe2x80x94NQ6xe2x80x94SO2Ar5; xe2x80x94NQ6xe2x80x94SO2Cy3; xe2x80x94OQ5; xe2x80x94OAr5; xe2x80x94OCy3; xe2x80x94OCOQ5; xe2x80x94OCOAr5; xe2x80x94OCOCy3; xe2x80x94COOQ5; xe2x80x94COOAr5; xe2x80x94COOCy3; xe2x80x94OCOOQ5; xe2x80x94OCOOAr5; xe2x80x94OCOOCy3; xe2x80x94CON(Q6)Q5; xe2x80x94CON(Q6)Ar5; xe2x80x94CON(Q6)Cy3; xe2x80x94CON(Q6)OQ5; xe2x80x94CON(Q6)OAr5; xe2x80x94CON(Q6)OCy3; xe2x80x94COQ5; xe2x80x94COAr5; xe2x80x94COCy3; xe2x80x94SQ5; xe2x80x94SAr5; xe2x80x94SCy3; xe2x80x94SOQ5xe2x80x94SOAr5; xe2x80x94SOCy3; xe2x80x94SO2Q5; xe2x80x94SO2Ar5; xe2x80x94SO2Cy3; xe2x80x94SON(Q6)Q5; xe2x80x94SON(Q6)Ar5; xe2x80x94SON(Q6)Cy3; xe2x80x94SO2N(Q6)Q5; xe2x80x94SO2N(Q6)Ar5; xe2x80x94SO2N(Q6)Cy3; xe2x80x94SO3H; xe2x80x94NO2; xe2x80x94CN;
xe2x80x83wherein
R29, R30, R31, and R32 are independently hydrogen, alkyl, alkenyl, alkynyl;
Q5, Q6, Q7, and Q8 are independently hydrogen, alkyl, alkenyl and alkynyl wherein the alkyl, the alkenyl and the alkynyl are optionally substituted by one or more groups selected from the following group:
halogen; xe2x80x94Ar6; Cy4; xe2x80x94N(R29)R30; xe2x80x94N(R30)Ar6; xe2x80x94N(R30)Cy4; xe2x80x94NR32xe2x80x94C(NR31)N(R30)R29; xe2x80x94NR32xe2x80x94C(NR31)N(R30)Ar6; xe2x80x94NR32xe2x80x94C(NR31)N(R30)Cy4; xe2x80x94NR31xe2x80x94CON(R30)R29; xe2x80x94NR31xe2x80x94CON(R30)Ar6; xe2x80x94NR31xe2x80x94CON(R30)Cy4; xe2x80x94NR30xe2x80x94COOR29; xe2x80x94NR30xe2x80x94COOAr6; xe2x80x94NR30xe2x80x94COOCy4; xe2x80x94OCON(R30)R29; xe2x80x94OCON(R30)Ar6; xe2x80x94OCON(R30)Cy4; xe2x80x94NR30COR29; xe2x80x94NR30xe2x80x94COAR6; xe2x80x94NR30xe2x80x94COCy4; xe2x80x94NR30SOR29; xe2x80x94NR30xe2x80x94SOAR6; xe2x80x94NR30xe2x80x94SOCy4; xe2x80x94NR30xe2x80x94SO2R29; xe2x80x94NR30xe2x80x94SO2Ar6; xe2x80x94NR30xe2x80x94SO2Cy4; xe2x80x94OR25; xe2x80x94OAr6; xe2x80x94OCy4; xe2x80x94COOR29; xe2x80x94COOAr6; xe2x80x94COOCy4; xe2x80x94OCOR29; xe2x80x94COAr5; xe2x80x94OCOCy3; xe2x80x94OCOOR29; xe2x80x94OCOOAr6; xe2x80x94Z1xe2x80x94OCOOCy4; xe2x80x94CON(R30)R29; xe2x80x94CON(R30)Ar6; xe2x80x94CON(R30)Cy4; xe2x80x94CON(R30)OR29; xe2x80x94CON(R30)OAr6; xe2x80x94CON(R30)OCy4; xe2x80x94COR29; xe2x80x94COAr6; xe2x80x94COCy4; xe2x80x94SR29; xe2x80x94SAr6; xe2x80x94SCy4; xe2x80x94SOR29; xe2x80x94SOAr6; xe2x80x94SOCy4; xe2x80x94SO2R29; xe2x80x94SO2Ar6; xe2x80x94SO2Cy4; xe2x80x94SON(R30)R29; xe2x80x94SON(R30)Ar6; xe2x80x94SON(R30)Cy4; xe2x80x94SO2N(R30)R29; xe2x80x94SO2N(R30)Ar6; xe2x80x94SO2N(R30)Cy4; xe2x80x94SO3H; xe2x80x94NO2; xe2x80x94CN;
or Q5 may be jointed with Q6 or Q7 to form, with the carbon atom which they attach, optionally substituted heterocycloalkane.
Ar5 and Ar6 are independently aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by one or two groups which are the same as the xe2x80x9csubstituentxe2x80x9d of the substituted aryl, the substituted heteroaryl, the substituted ortho-arylene and substituted ortho-heteroarylene, and xe2x80x9csubstituentxe2x80x9d of R8, R9, and R14;
Cy3 and Cy4 are independently cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein the cycloalkyl, the cycloalkenyl, the heterocycloalkyl, and the heterocycloalkenyl are optionally substituted by one or two groups which are the same as the substituent of the substituted phenyl as used in Ar3 or Ar4.
The number of xe2x80x9csubstituentxe2x80x9d of substituted alkyl is one to five, preferably one, two, or three.
When R1 is xe2x80x94(CHR4)nxe2x80x94(CR5R6)xe2x80x94COxe2x80x94NHOH in formula 1, xe2x80x94(CHR4)n1xe2x80x94(CR5R6)xe2x80x94CONHOH in formula 2, xe2x80x94(CHR4)n2xe2x80x94(CR5R6)xe2x80x94COxe2x80x94NHOH in formula 3 and 3xe2x80x2, and R5 or R6 are 1-substituted alkyl in formula 1, 2, 3, and 3xe2x80x2, the substituents of R5 or R6 do not include the following groups:
xe2x80x94CON(Q6)Q5; xe2x80x94CON(Q6)Ar5; xe2x80x94CON(Q6)Cy3xe2x80x94CON(Q6)OQ5; xe2x80x94CON(Q6)OAr5; xe2x80x94CON(Q6)OCy3; xe2x80x94COxe2x80x94Q5 
xe2x80x83wherein
Q5, Q6, Ar5, and Cy3 are described above.
xe2x80x9cHalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine. Typical examples are chlorine and fluorine.
The preferable examples of xe2x80x94(CHR4)nxe2x80x94(CR5R6)xe2x80x94COxe2x80x94NHOH as used in one of R1 and R3 in formula 1; xe2x80x94(CHR4)n1xe2x80x94(CR5R6)xe2x80x94COxe2x80x94NHOH as used in formula 2; or xe2x80x94(CHR4)n2xe2x80x94(CR5R6)xe2x80x94COxe2x80x94NHOH as used in formula 3 are 
wherein R5 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and more preferably hydrogen or optionally substituted alkyl;
n3 is an integer of 0 to 3; n4 is an integer of 0 to 2, and more preferable n3 and n4 is 0;
A3 is cyclopentane or cyclohexane;
and A4 is cyclopentane, cyclohexane, tetrahydropyrane, piperazine and the like.
The preferable R6 in formula 1, 2, 3, and 3xe2x80x2 is hydrogen or C1-C3 alkyl such as methyl, ethyl.
The more preferable example of R5 in formula 2 is the optionally substituted alkyl. The functional groups of the xe2x80x9csubstituentsxe2x80x9d of substituted alkyl, such as hydroxy, carboxyl, amino, or thiol, may be protected with typical protective groups described in xe2x80x9cprotective groups in organic synthesis 2nd edition by W. Greene (John Wiley and Sons, INC.)xe2x80x9d.
The more preferable R5 in formula 3 and 3xe2x80x2 is hydrogen or alkyl such as methyl, ethyl, propyl, and isopropyl.
The preferable examples of the hydroxamic acid derivative represented by formula 1 are
(1) the derivatives wherein R1 is xe2x80x94(CHR4)nxe2x80x94(CR5R6)xe2x80x94CONHOH; and R3 is hydrogen, or optionally substituted alkyl; and
(2) the derivatives wherein R1 is alkyl substituted by a) halogen, b)optionally substituted cycloalkyl, c) optionally substituted aryl, d)optionally substituted hetero-cycloalkyl or e)optionally substituted heteroaryl; and R3 is xe2x80x94(CHR4)nxe2x80x94(CR5R6)xe2x80x94CONHOH;
wherein n, R4, R5, and R6 are as defined above.
The preferable example of R2 in formula 1; R10 in formula 2; and R12 in formula 3 and 3xe2x80x2 are hydrogen or alkyl such as methyl and ethyl.
The preferable examples of the hydroxamic acid derivative represented by formula 2 are the derivatives wherein R11 is hydrogen or optionally substituted alkyl, such as methyl, ethyl, propyl or butyl in which the xe2x80x9csubstituentsxe2x80x9d are selected from the following group;
xe2x80x94NQ6xe2x80x94COOQ5; xe2x80x94NQ6xe2x80x94COOAr5; xe2x80x94NQ6xe2x80x94COOCy3; xe2x80x94NQ6xe2x80x94COQ5; xe2x80x94NQ6xe2x80x94COAr5; xe2x80x94NQ6xe2x80x94COCy3; xe2x80x94NQ6xe2x80x94SOQ5; xe2x80x94NQ6xe2x80x94SOAr5; xe2x80x94NQ6xe2x80x94SOCy3; NQ6xe2x80x94SO2Q5xe2x80x94; xe2x80x94NQ6xe2x80x94SO2Ar5; xe2x80x94NQ6xe2x80x94SO2Cy3; xe2x80x94COOQ5xe2x80x94; xe2x80x94COOAr5xe2x80x94; xe2x80x94COOCy3xe2x80x94; xe2x80x94CON(Q6)Q5; xe2x80x94CON(Q6)Ar5; xe2x80x94CON(Q6)Cy3; xe2x80x94CON(Q6)OQ5; xe2x80x94CON(Q6)OAr5; xe2x80x94CON(Q6)OCy3; xe2x80x94COQ5; xe2x80x94COAr5; xe2x80x94COCy3; xe2x80x94SOxe2x80x94Q5; xe2x80x94SOxe2x80x94Ar5; xe2x80x94SOxe2x80x94Cy3; xe2x80x94SO2xe2x80x94Q5; xe2x80x94SO2xe2x80x94Ar5; xe2x80x94SO2xe2x80x94Cy3; xe2x80x94SON(Q6)xe2x80x94Q5; SON(Q6)xe2x80x94Ar5; SON(Q6)xe2x80x94Cy3; xe2x80x94SO2N(Q6)xe2x80x94Q5; xe2x80x94SO2N(Q6)xe2x80x94Ar5; xe2x80x94SO2N(Q6)Cy3;
xe2x80x83wherein
Ar5, Cy3, Q5 and Q6 are described above.
The more preferable xe2x80x9csubstituentsxe2x80x9d are selected from the following group;
xe2x80x94COOQ5; xe2x80x94COOAr5; xe2x80x94COOCy3; xe2x80x94CON(Q6)Q5; xe2x80x94CON(Q6)Ar5; xe2x80x94CON(Q6)Cy3; xe2x80x94CON(Q6)OQ5; xe2x80x94CON(Q6)OAr5; xe2x80x94CON(Q6)OCy3; xe2x80x94COxe2x80x94Q5; xe2x80x94COxe2x80x94Ar5; xe2x80x94COxe2x80x94Cy3; xe2x80x94COOxe2x80x94Q5; xe2x80x94COOxe2x80x94Ar5; xe2x80x94COOxe2x80x94Cy3;
xe2x80x83wherein
Ar5, Cy3, Q5 and Q6 are described above.
The preferable example of the hydroxamic acid derivative represented by formula 3 and 3xe2x80x2 are the derivatives wherein R13 is optionally substituted alkyl, such as methyl, ethyl, or propyl. The xe2x80x9csubstituentsxe2x80x9d are selected from the following groups;
xe2x80x94Ar5; xe2x80x94Cy3; xe2x80x94Oxe2x80x94Q9; xe2x80x94OAr5; xe2x80x94N(Q5)Ar5; xe2x80x94Sxe2x80x94Q9; xe2x80x94SAr5;
xe2x80x83wherein
Ar5, Cy3, and Q5 are described above;
Q9 is alkyl, alkenyl or alkynyl wherein the alkyl, the alkenyl and the alkynyl are substituted by one or more groups selected from the following group:
xe2x80x94Ar6; Cy4; xe2x80x94OAr6; xe2x80x94SAr6;
xe2x80x83wherein
Ar6, and Cy4 are described above;
The preferable Ar5 and Ar6 in R13 in formula 3 and 3xe2x80x2 are optionally substituted phenyl or optionally substituted monocyclic heteroaryl such as pyridyl, thienyl, furyl and pyrrolyl. The preferable xe2x80x9csubstituentsxe2x80x9d are selected from the following groups;
halogen; halogenated alkyl; xe2x80x94OQ1; xe2x80x94OAr3; xe2x80x94SQ1; or xe2x80x94SAr3 
wherein Q1 and Ar3 are as defined above.
The preferable positions of the substituents of the substituted phenyl and the substituted monocyclic heteroaryl in R13 in formula 3 and 3xe2x80x2 are m-position or p-position, especially p-position.
The preferable Ar2 in formula 2 are optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein the xe2x80x9csubstituentsxe2x80x9d are selected from the following groups;
halogen, alkyl, halogenated alkyl, xe2x80x94OQ1, xe2x80x94OAr3, xe2x80x94SQ1, xe2x80x94SAr3, xe2x80x94SOQ1, xe2x80x94SOAr3, xe2x80x94SO2Q1, xe2x80x94SO2Ar3;
xe2x80x83wherein
Ar3 and Q1 are defined above.
The preferable positions of the substituent of the substituted phenyl and the substituted monocyclic heteroaryl as used in Ar2 in formula 2 are n-position or p-position, especially p-position. More preferable Ar2 in formula 2 are phenyl or monocyclic heteroaryl.
The preferable A1 in formula 3 and 3xe2x80x2 are phenylene or monocyclic hteroarylene, such as pyrazole-3,4-diyl, imidazole-4,5-diyl, and thiophene-2,3-diyl.
When the A1 in formula 3 and 3xe2x80x2 is phenylene, the preferable positions of R8 or R9 in formula 3, and R14 or R15 in formula 3xe2x80x2 are 6th and/or 7th positions. 
The hydroxamic acid derivatives can be prepared through three processes:
[A] cyclization process;
[B] substitution process;
[C] process of forming hydroxamic acid group.
The order of three processes may be the same as or different from the order [A], [B] and [C] as long as the hydroxamic acid derivatives can be prepared. And protective groups may be used through these processes to protect functional groups in the hydroxamic acid derivative. Protective groups include well known groups described in xe2x80x9cProtective Groups Inorganic Synthesesxe2x80x9d 2nd ed. T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. 1991.
(1) 5-Membered Ring 
wherein RA, RB and RL are independently hydrogen atom or substituent; and Y2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
5-Membered ring can be formed for example by cyclization reaction of imine with mercapto- or hydroxy-carboxylic acid by the same method as ones described in Chem. Rev., Vol.81, 175 (1981). One to 5 equivalents of mercapto- or hydroxy-carboxylic acid per equivalent of the imine is preferably used. In this reaction, dehydration agent such as molecular sieves 3A (MS 3A) or triethyl orthoformate may be added. Reaction solvent includes for example ether such as THF; halogenated hydrocarbon such as chloroform, dichloromethane; amide such as DMF, N-methyl-pyrrolidone; sulfone or sulfoxide such as tetramethylene solfone, DMSO; hydrocarbon such as benzene, toluene, xylene, heptane, hexane; or mixture thereof. Reaction temperature is usually 50xc2x0 C. to boiling point of the solvent. The imine can be prepared by a conventional method.
(2) 6-Membered Ring
6-Membered ring can be formed for example by the same methods as ones described in EP 162776 A ; Chem. Pharm. Bull., 39, 2888 (1991); ibid., 42, 1264 (1994); ibid., 44, 2055 (1996). 
wherein RC, RD and RM are independently hydrogen atom or substituent, or RCxe2x80x94Cxe2x80x94Cxe2x80x94RD is optionally substituted ortho-arylene or optionally substituted ortho-heteroarylene; and
X1 is chlorine, bromine or iodine.
6-Membered ring can be formed by amidation reaction of hydroxy-amine with halo-carboxylic acid or halo-ester, followed by ether formation reaction. Amidation reaction can be performed by a conventional method such as dehydration method, mixed anhydride method, activated ester method and the like (xe2x80x9cThe Peptides Analysis, Synthesis, Biologyxe2x80x9d, Vol.1, 2, 3, 5, ed. by E. Gross, J. Meinhofer Academic Press (1979)). Dehydration agent used in the dehydration method includes dicyclohexylcarbodiimide, N,N-dimethylaminopropyl-Nxe2x80x2-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. Acylation agent used in mixed anhydride method includes isobutyl chloroformate, pivaloyl chloride and the like. Ether formation reaction can be carried out by a conventional method. 
wherein RC, RD, RM and X1 are as defined above; and RE is hydrogen or alkyl.
6-Membered ring can be formed by thioether formation reaction of mercaptoamine and halide, followed by amidation reaction. Thioether formation reaction may be performed in the presence of base such as K2CO3, NaOH and triethylamine. 2-Mercapto-anilines may be commercially available or can be prepared from 2-aminothiazoles, 2-methylthiazoles, or dithiazolium chloride by the same method as one described in Chem. Pharm. Bull., 39, 2888 (1991); ibid, 42, 1264 (1994); ibid, 44, 2055 (1996); J. Chem. Soc., 1948, 870. The amidation reaction can be carried out by heating in the presence of acid such as HCl, HBr, H2SO4, acetic acid and methanesulfonic acid, or by a conventional method described above. 
wherein RC, RD, Y2, RE, RM and X1 are as defined above.
6-Membered ring can be formed by ether or thioether formation reaction of nitrohalide and thiol or alcohol, followed by reduction and amidation reaction. Ether or thioether formation reaction may be performed in the presence of base such as K2CO3, NaOH and triethylamine. Reduction may be carried out by a conventional method. Amidation reaction may be carried out by heating in the presence of acid or by a conventional method described above. 
wherein RC, RD, RM, Y2 and X1 are as defined above; and X2 is chlorine, bromine or iodine; and RF is hydrogen or substituent.
6-Membered ring can be formed by ether or thioether formation reaction of alcohol or thiol and halide, followed by cyclization reaction. Ether or thioether formation reaction can be carried out by the method described above. Cyclization reaction can be performed in the presence of Pd catalyst by the same method as one described in J. Am. Chem. Soc., 119, 8451-8458 (1997). Base such as Cs2CO3 may be added in this reaction.
(1) Substitution at the Position of R1 in the Formula [1]
Introducing a substituent at the position of R1 in the formula [1] can be performed for example by alkylation. Alkylation may be performed by reacting with corresponding alkyl halide, preferably alkyl iodide or bromide, in the presence of base such as NaH, NaOMe, potassium t-butoxide and Na2CO3. Reaction solvent is for example ether such as THF; amide such as DMF; sulfoxide such as DMSO or mixture thereof, preferably THF and DMF. Reaction temperature is usually 0xc2x0 C. to 160xc2x0 C.
(2) Substitution at the Position of R2 and R3 in the Formula [1]
Introducing substituent(s) at the position of R2 and R3 in the formula [1] can be performed for example by aldol reaction, Wittig reaction, alkylation, Michael reaction and the like. 
wherein R1, X and Y are as defined above; and RG is hydrogen or substituent.
Aldol reaction may be performed by reacting with the corresponding aldehyde in the presence of base or acid (J. Med. Chem., 20, 729 (1977), EP 657444 (A), JP 7-233155 (A)). 
wherein R1, X, Y and RG are as defined above.
Wittig reaction may be performed by reacting with the corresponding aldehyde (J. Org. Chem., 40, 1731 (1975), U.S. Pat. No. 3,873,535, U.S. Pat. No. 3,923,709).
(2) Introduction of Sulfoxide and Sulfone
Introduction of sulfoxide can be carried out by oxidizing thioether group with mild oxidizing agent such as hydrogen peroxide, sodium periodate and the like. Introduction of sulfone can be carried out by oxidizing thioether or sulfoxide with oxidizing agent such as m-chloroperbenzoic acid(m-CPBA) and potassium peroxymonosulfate.
Hydroxamic acid group can be formed for example by (1) amidation of ester group with hydroxylamine (J. Med. Chem., 40, 2525 (1997)) or (2) condensation of carboxylic acid group with protected hydroxylamine followed by deprotection (J. Med. Chem., 41, 1209 (1998); Ibid., 41, 1745 (1998); Ibid., 38, 2570 (1995)).
(1) Amidation of Ester Group With Hydroxylamine
xe2x80x94CO2RH+NH2OHxe2x86x92xe2x80x94CONHOH
wherein RH is optionally substituted alkyl such as methyl, ethyl and benzyl.
Preferred RH is methyl or ethyl. Two to 50 equivalents of hydroxylamine per equivalent of the ester group is preferably used. Reaction solvent is for example alcohol such as methanol, ethanol; amide such as DMF; sulfoxide such as DMSO; ketone such as acetone; water or mixture thereof, especially alcohol. Reaction temperature is usually 0xc2x0 C. to 80xc2x0 C.
(2) Condensation of Carboxylic Acid Group With Protected Hydroxylamine Followed by Deprotection
xe2x80x94CO2H+NH2ORJxe2x86x92xe2x80x94CONHOH
wherein RJ is a protective group of hydroxylamine such as t-butyldimethylsilyl, trimethylsilyl, t-butyl, benzyl, 4-methoxybenzyl and tetrahydropyranyl.
Condensation of carboxylic acid group with protected hydroxylamine can be performed by a conventional method as described above. The protective group of the protected hydroxamic acid group can be removed by a conventional method (xe2x80x9cProtective Groups in Organic Synthesesxe2x80x9d 2nd ed. T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. 1991).
The prodrug of the hydroxamic acid derivative includes the prodrugs described in Chemistry and Industry, 1980, 435; Advanced Drug Discovery Reviews 3, 39(1989). The typical examples are biohydrolyzable esters such as acyloxymethyl esters, glycolates, lactates and morpholinoethyl ester of carboxyl group; hemiglutarates of phenolic hydroxyl group; N-morpholinomethyl amides; N-acyloxymethyl amines; N-ayloxyalkoxycarbonylamines.
The present invention includes every isomers such as diastereomers, enantiomers, and geometrical isomers, if the hydroxamic acid derivative has such isomers.
Method of optical resolution of a present invention compound or an intermediate thereof which has acidic group comprises steps of
(1) a step of forming a salt of a compound of present invention or intermediate thereof and an optically active base;
(2) a step of recrystallization.
Examples of the solvent forming a salt are an alcohol solvent (such as methanol, ethanol 2-propanol and the like), an ether solvent (such as diethyl ether and the like), an aromatic hydrocarbon solvent (such as toluene and the like), an aprotic solvent (such as acetonitrile), and a mixture of the solvent described before. Examples of the optical active base are an organic amine (such as xcex1-phenetylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, and the like), and the like.
Method of optical resolution of a present invention compound or an intermediate thereof which has basic group comprises steps of
(1) a step of forming a salt of a compound of present invention or intermediate thereof and an optically active acid;
(2) a step of recrystallization.
Examples of the solvent forming a salt are an alcohol solvent (such as methanol, ethanol 2-propanol and the like), an ether solvent (such as diethyl ether and the like), an aromatic hydrocarbon solvent (such as toluene and the like), an aprotic solvent (such as acetonitrile), and a mixture of the solvent described before. Examples of the optical active acid are a monocarboxylic acid (such as mandelic acid, N-benzyl alanine, lactic acid and the like), a dicarboxylic acid (such as tartaric, acid, O-diisopropylidene tartaric acid, malic acid and the like), a sulfonic acid (such as camphor sulfonic acid, bromocamphor sulfonic acid and the like), and the like.
Temperature of forming the salt is selected from the range from about room temperature to about boiling point of the solvent. To increase the purity of optical isomer, it is preferable to heat the solution of salts to around the boiling point of solvent. A molar rate of optically active acid and the compound or the intermediate is selected from the range of about 0.5 to about 2.0, preferably around 1.0. If it is necessary to improve the optical purity, it is possible to repeat recrystallization in the solvent described before.
The present invention also includes solvates such as the hydrate and the like, of the hydroxamic acid derivative or the prodrug thereof, or the pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts of the hydroxamic acid derivative or the prodrug thereof include, for example, salts with inorganic acids such as the hydrochloride, hydrobromide, sulfate, phosphate and the like; salts with organic acids such as the acetate, oxalate, citrate, lactate, tartrate, malonate, fumarate, maleate, mathanesulfonate and the like; salts with inorganic metals such as the lithium salt, sodium salt, potassium salt, magnesium salt, aluminum salt, barium salt and the like; salts with organic bases such as the ammonium salt, triethylammonium salt, tetrabutylammonium salt, pyridinium salt, pyrrolidinium salt, piperidinium salt and the like.
The hydroxamic acid derivatives or the prodrug thereof, or the pharmaceutically acceptable salt thereof of the present invention are useful as matrix metallo-proteinase inhibitors. Therefore, they may be used to treat or prevent a disease associated with excess or undesired matrix metallo-proteinases.
The diseases associated with excess or undesired matrix metallo-proteinases include, for example, the following diseases:
Abnormal wound healing, acne, acute coronary syndrome, acute infection, AIDS, alcoholism, allergic conjunctivitis, allergic reactions, allergic rhinitis, ALS, Alzheimer""s diseases, anaphylaxis, aneurysmal aortic disease, angina, angiofibromas, anorexia, aortic aneurysm, ARDS, aspirin-independent anti-thrombosis, asthma, atherosclerosis, atherosclerotic plaque rupture, atopic dermatitis, benign hyperplasia, bleeding, bone fractures, bronchitis, burns, cachexia, cancer, cardiac infarction, cardiac insufficiency, cardiomyopathy, cerebral hemorrhaging, cerebral ischemia, cerebral vascular dementia, CHF, chronic bronchitis, chronic dermal wounds, chronic obstructive pulmonary disease, cirrhosis, congestive heart failure, corneal injury, coronary thrombosis, Crohn""s disease, cystic fibrosis, decubitis ulcer, diabetic peripheral neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne""s muscular dystrophy, emphysema, endometriosis, endosclerosis, epidermolysis bullosa, eye disorders, fibrosis, gastritis, gingivitis, glomerular diseases, glomerulonephritis, gout, graft rejection, gum disease, GVHD, Hashimoto""s thyroiditis, head trauma, headaches, heart attacks, heart failure, hemangiomas, hemorrhage, hepatitis, hirsutism, Huntington""s disease, hypertension, insulin resistance, interstitial nephritis, ischemia, ischemic heart disease, Kaposi""s sarcoma, keratinization, keratitis, kidney failure, leishmaniasis, leprosy, leukemia, leukocyte infiltration, liver cirrhosis, loss of appetite, macular degeneration, malaria, mandibular joint disease, memory impairment, meningitis, migraine, miscarriage, multi-infarct dementia, multiple sclerosis, muscular dystrophy, myalgia, myasthenia gravis, myelinic degradation, myocardial infarction, myopia, neovascular glaucoma, neuroinfalmmation, ocular tumors, optic neuritis, osteoarthritis, osteopenia, Paget""s disease, pain, pancreatitis, Parkinson""s disease, periodontitis, peripheral vascular disease, polyarteritis nodositas, polychondritis, premature childbirth, premature rupture of fetal membranes, prion disease, proliferative retinopathies, proteinurea, pseudogout, psoriasis, pterygium, pulmonary emphysema, radiation damage, rattle snake bite, Reiter""s syndrome, renal fibrosis, reocclusion, reperfusion injury, restenosis, scleritis, scleroderma, senile dementia, senility, sepsis, septic shock, Sharp syndrome, Sjoegren""s syndrome, SLE, spondylosis, stenosis, sterility, stroke, system sclerosis, thrombosis, toxic effects of chemotherapy, toxic shock, tuberculosis, ulcerations (corneal, epidermal, gastric), ulcertive colitis, uremia, vasculitis, ventricular dilation, vesicular epidermolysis.
The hydroxamic acid derivative or the prodrug thereof, or the pharmaceutically acceptable salt thereof may be administered orally or parenterally. Pharmaceutical forms for oral administration include for example tablets, pills, capsules, powders, granules, suspensions, emulsions, syrups and the like. Pharmaceutical forms for parenteral administration include for example intravenous injections such as drops, intramuscular injections, subcutaneous injections, intranasal preparations, eye drops, suppository, percutaneous preparations such as ointments, creams, lotions, and the like.
The solid compositions such as tablets can be prepared by mixing the active compound with pharmaceutically acceptable conventional carriers or excipients such as lactose, sucrose, corn starch or the like; binders such as hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose or the like; disintegrating agents such as sodium carboxymethylcellulose, sodium starch glycolate or the like; lubricants such as stearic acid, magnesium stearate or the like; or preservatives or the like.
For parenteral administration, the active compound can be dissolved or suspended in a physiologically acceptable carrier such as water, saline, oil, dextrose solution or the like, which may contain auxiliary agents such as emulsifiers, stabilizers, salts for influencing osmotic pressure or buffers, if desired.
The dose for administration varies widely depending on the grade of the symptoms, the patient""s age, body weight, sex, administration route, and the like. But the hydroxamic acid derivative is usually administered to an adult (ca. 60 kg) in a dose of approximately 1-1,000 mg, preferably 5-300 mg once or several times per day, by the oral route. By the parenteral route, the hydroxamic acid derivative is usually administered to an adult (ca. 60 kg) in a dose of approximately 0.1-200 mg, preferably 0.3-100 mg once or several times per day.